Process for the preparation of phenylethanolaminotetralins

ABSTRACT

A process for the preparation of phenylethanolaminotetralins of formula ##STR1## wherein X is hydrogen, a halogen, a trifluoromethyl or a lower alkyl group and R o  is hydrogen or a methyl group substituted by a carboxy or a lower carbalkoxy group, which comprises treating a mandelic acid with a 2-amino-7-hydroxytetralin, optionally alkylating with a lower alkyl haloacetate and reducing the amido group of the mandelamide into a methyleneamino group. The mandelamides intermediates are novel.

This application is a division of application Ser. No. 07/603,247, filedOct. 25, 1990, now U.S. Pat. No. 5,198,586, which is a continuation ofapplication Ser. No. 07/231,374, filed Aug. 11, 1988, now abandoned.

The present invention provides a process for the preparation ofphenylethanolaminotetralins, more particularly by amidation of amandelic acid with an aminotetralin and by reduction, and theintermediates used in this process.

The European patent Specification 211721 disclosesphenylthanolaminotetralins of formula ##STR2## wherein X is hydrogen,halogen, a trifluoromethyl group or a lower alkyl group and R ishydrogen; a lower alkyl group unsubstituted or substituted by acycloalkyl group of from 3 to 7 carbon atoms, a hydroxy group, a loweralkoxy, carboxy or lower carbalkoxy group; a cycloalkyl group of from 3to 7 carbon atoms; or a lower alkanoyl group and their pharmaceuticallyacceptable salts.

According to this document, the compounds of formula (A) and theirpharmaceutically acceptable salts have interesting pharmacologicalproperties, the compounds bearing the OR substitutent in 7 position ofthe tetralin ring having revealed a particularly marked lipolyticactivity.

In the present description:

the term "lower alkyl", designates a monovalent radical of a saturatedhydrocarbon containing from 1 to 4 carbon atoms, such as methyl, ethyl,propyl, isopropyl or n-butyl;

the term "lower carbalkoxy", designates the carboxyl group esterifiedwith a lower alkyl as defined hereinabove;

the term "halogen" includes the four halogens fluorine, chlorine,bromine, iodine, the first three being particularly preferred;

the terms "tetralin" and "tetralone" are referred to1,2,3,4-tetrahydronaphtalene.

According to the above European Patent Specification, the products offormula (A) are prepared following different preparative methods thatalways involve a reaction of a 2-aminotetralin or a 2-oxotetralin with

a phenylethanolamine or

an epoxystyrene or

a phenylglyoxal or

an alpha-haloacetophenone.

Among the preparative methods of the products of formula (A)hereinabove, an O-alkylation is described that, starting from2-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-phenylethanol orfrom2-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-(3-chlorophenyl)ethanol,by reaction with ethyl bromoacetate gives the2-[(7-carbethoxymethoxy-1,2,3,4-tetrahydronaphth-2-yl)-amino]-1-phenylethanolor the2-[(7-carbethoxymethoxy-1,2,3,4-tetrahydronaphth-2-yl)-amino]-1-(3-chlorophenyl)ethanol.This reaction does not actually give good results because the yield inend product is very low.

Still according to the above European Patent Specification, the productsof formula (A) may be prepared as diastereoisomers or optically purestereoisomers by using one or the two starting compounds in an opticallyactive form. However, the obtention of optically active stereoisomersgenerally involves further crystallizations of the final product thatlower the yields and, above all, a hard practical work.

It has now been found that if a 2-amino-7-hydroxytetralin is reactedwith a mandelic acid, there is obtained an amide as a mixture ofracemates that are in diastereoisomeric relationship each other and thatmay be easily separated.

It has also been found that the amides thus obtained may be reduced inorder to obtain the phenylethanolaminotetralins without any interferencewith the stereochemistry of the products.

It has further been found that starting from a racemic aminotetralin andfrom an optically active mandelic acid, or vice-versa, there is obtainedan amide as a mixture of diastereoisomers easily detectable andseparable by chromatography that, after separation, give optically purephenylethanolaminotetralins by reduction.

It has finally been found that amides prepared by reaction of a mandelicacid with a 2-amino-7-hydroxytetralin may be O-alkylated by a loweralkyl haloacetate in very good yields and that the product thus obtainedmay be reduced in order to prepare the correspondingO-carbalkoxymethylphenylethanolaminotetralin in a global yield higherthan that of the O-alkylation described in EP 211 721.

Thus, the present invention provides a process for the preparation ofphenylethanolaminotetralins of formula ##STR3## wherein X is as definedhereinabove and R^(o) is hydrogen or a methyl group substituted by acarboxy or a lower carbalkoxy group, and of their pharmaceuticallyacceptable salts, which comprises reacting a functional derivative of amandelic acid of formula ##STR4## wherein X is as defined hereinabove,with an aminotetralin of formula ##STR5## the mandelamine thus obtainedof formula ##STR6## wherein X is as defined hereinabove, is then,submitted to a reduction for the transformation of the amido group intothe methyleneamino group or alternatively treated with a lower alkylhaloacetate in the presence of a basic condensation agent, the abovementioned haloacetate being a bromo-, chloro- or iodoacetate; on thissecond assumption submitting the resulting product, in any order to areduction for the transformation of the amido group into a methyleneamino group and, if desired, to a saponification of the lower carbalkoxygroup into the carboxy group; and, if desired, transforming the productthus obtained into one of its pharmaceutically acceptables salts.

Among the compounds that may be prepared following the process of thepresent invention, those of formula I wherein X is as definedhereinabove and R^(o) is hydrogen or a carbethoxymethyl group areparticularly preferred.

The chloride, the anhydride, a mixed anhydride, an active ester or afree acid suitably activated, for example, with dicyclohexylcarbodiimideor with hexafluorophosphate ofbenzotriazolyl-N-oxytris(dimethylamino)phosphonium (BOP) may be used asa functional derivative. A mandelic acid activated with a condensingagent such as BOP is preferably used as a starting compound.

The reaction of the functional derivative of mandelic acid with the2-amino-7-hydroxytetralin of formula III hereinabove is carried out inan organic solvent such as methylene chloride, optionally in thepresence of a proton acceptor such as triethylamine.

Preferably, an equimolecular amount of mandelic acid, BOP andaminotetralin is used.

Thus, the corresponding mandelamide of formula IV is obtained that isisolated and, if desired, separed into its diastereoisomers. Thisseparation is carried out by chromatography and each stereoisomer thusseparated may be used for the following step.

Thus, starting from a racemic mandelic acid (II) and from a racemic2-amino-7-hydroxytetralin (III), a mixture of mandelamidediastereoisomers is obtained that, by separation, gives the couple ofRR,SS and RS,SR diastereoisomers.

Starting, for example, from an optically active mandelic acid and from aracemic (III) aminotetralin, there is obtained a mandelamide of formulaIV as a couple of (RR+RS) or (SS+SR) diastereoisomers that, afterseparation, gives the (RR) and (RS) or (SS) and (SR) pure enantiomers.

A (R)-mandelic acid is used as advantageous starting product, preferablythe (R)-3-chloromandelic acid. The racemic 3-chloromandelic acid canalso be used.

If the starting mandelic acid is in racemic form, the aminotetralin offormula III will be preferably used in optically active form.

Particularly preferred aminotetralins are

(R)-2-amino-7-hydroxy-1,2,3,4-tetrahydronaphtalene and

(S)-2-amino-7-hydroxy-1,2,3,4-tetrahydronaphtalene.

A racemic 2-amino-7-hydroxy-1,2,3,4-tetrahydronaphtalene can also beused.

The mandelamide of formula IV may be directly submitted to a reductionfor the transformation of the amido group into the methyleneamino group;alternatively the mandelamine is treated with a lower alkyl haloacetatein alkaline medium. The O-alkylation reaction is carried out accordingto the known techniques using a lower alkyl chloro- acetate,bromoacetate or iodoacetate, the bromoacetate being preferred. An alkalimetal hydroxide or carbonate, for example potassium carbonate, may beused as an alkaline condensing agent and the reaction may be carried inthe presence of a catalytic agent such as potassium iodide. The (lowercarbalkoxy)methyl ether of the amide IV is isolated in very good yieldsaccording to the conventional techniques.

The product thus obtained may be directly submitted to a reduction ofthe amido group into a methyleneamino group, or it may be saponified inorder to transform the lower carbalkoxy group into the free or salifiedcarboxy group according to well known techniques.

Thus, the reduction of the amido group into the methyleneamino group maybe carried out on a mandelamide of formula ##STR7## wherein X and R^(o)are as defined hereinabove.

The reduction step of the mandelamide of formula IVa is carried out, forexample, by action of an hydride, such as lithium aluminium hydride orof diborane, more particularly by action of a reagent generatingdiborane such as the complex between borane and dimethylsulfide,hereinafter designated "borane-methylsulfide". The reaction is carriedout in an organic solvent, such as tetrahydrofuran and the compound offormula I is isolated according to the known techniques.

In case of reduction of a mandelamide of formula IVa wherein R^(o) is amethyl substituted by an optionally salified carboxy group or, moreparticularly, by a lower carbalkoxy group, this group may be alsoreduced into the alcohol. Thus, in this case, the use of a reducingreagent that allows to obtain, at least preferably, the selectivereduction of the amido group, is preferred. In any case, moreparticularly when a mandelamide of formula IVa, wherein R^(o) is amethyl substituted by a carbalkoxy group, is reduced, there is obtaineda mixture of the product of formula I wherein R^(o) is a methylsubstituted by the corresponding lower carbalkoxy group and of a productof formula ##STR8## wherein X is as defined hereinabove.

The products of formula Ia are novel and have a good activity on theintestinal motility.

If borane-methylsulfide is used as reducing agent and the reaction iscarried out at low temperature (15°-25° C.) the reduction of the amidogroup is preferably obtained and the corresponding compound of formulaI, wherein R^(o) is a lower carbalkoxy or carboxy substituted methylgroup, is obtained in global yields higher than those described in EP211 721.

The reduction reaction respects the stereochemistry of the mandelamideIVa and the products of formula I may be thus obtained as a racemicmixture or as diastereoisomers or optically pure isomers starting fromthe appropriate mandelamide.

The 2-amino-7-hydroxytetralin of formula III is prepared starting fromthe corresponding methoxytetralone of formula ##STR9## by reaction withbenzylamine, reduction of the resulting benzylimine by sodiumborohydride, debenzylation by catalytic hydrogenation and demethylationby 48% hydrobromic acid.

The two optically active forms of the aminotetralins of formula III areprepared by resolution of the racemates according to known methods, forexample by salification with an optically active acid, preferablymandelic acid.

The mandelamides of formula IVa hereinabove are novel and represent thekey intermediates of the process of the present invention.

Thus, it is another object of the present invention to provide compoundsof formula IVa, in racemic form or in form of their separatedstereoisomers.

The following examples illustrate the invention without, however,limiting it. The specific optical rotation symbol is indicated as[alpha], but it must be read [alpha]_(D) ²⁰.

PREPARATION I 2-amino-7-hydroxytetralin hydrobromide; SR 58518 A.

(a) A mixture of 8 g of 7-methoxy-2-tetralone, 4.8 g of benzylamine, 150ml of anhydrous toluene and 100 mg of p.toluenesulfonic acid is heatedwith reflux. The residual oil is evaporated to dryness, taken up with100 ml of methanol then 8.5 g of sodium borohydride are carefully addedto the solution at 0°-5° C. The mixture is left under stirring at roomtemperature overnight, then 50 ml of water are added thereto. Thesolution is left under stirring for 30 minutes, the solvent isevaporated, the residue is taken up with 30 ml of water and 10 ml of aconcentrated ammonium hydroxide solution. The product is extracted with200 ml of ethyl acetate, the organic phase is dried over sodium sulfate,filtered and evaporated to dryness. A dark oil is obtained that ispurified by flash chromatography (elution with a 95/5 mixture of ethylacetate/methanol). The base thus obtained is transformed into itshydrochloride by dissolving it in 40 ml of isopropanol and by addingisopropanol saturated with hydrogen chloride. Thus, there is obtained11.4 g of 7-methoxy-2-benzylamino-1,2,3,4-tetrahydronaphtalenehydrochloride; m.p. 265°-267° C. (dec.).

(b) The above product, dissolved in 200 ml of methanol and 100 ml ofwater, is submitted to a hydrogenation in presence of 1.2 g of 10%palladium charcoal, under atmospheric pressure at 45°-50° C. After 4hours the mixture is filtered, evaporated to dryness, taken up twicewith absolute ethanol and evaporated to dryness. A white solid isobtained that is taken up with 70 ml of isopropanol in the warm. Bycooling, the resulting suspension precipitates and gives 7.8 g of2-amino-7-methoxytetralin hydrochloride; m.p. 214°-216° C.

(c) An amount of 6.6 g of the above product is suspended in 80 ml of 48%hydrobromic acid and the mixture is heated with reflux for 2 hours. Thesolution is evaporated to dryness, then the residue is taken up withabsolute ethanol and evaporated to dryness twice. Thus, an oil isobtained that is dissolved in 20 ml of isopropanol in the warm. Byaddition of 30 ml of ethyl ether to the solution, there is obtained 6.8g of crystalline 2-amino-7-hydroxytetralin hydrobromide; m.p. 171°-173°C.

PREPARATION II R(+)-2-amino-7-hydroxytetralin monohydrate; SR 58554

To a solution in 550 ml of absolute ethanol of 50 g of2-amino-7-methoxytetralin as a raw base, obtained from the correspondinghydrochloride (PREPARATION I b) by neutralisation with 10% sodiumhydroxide, extraction with ethyl acetate and evaporation of the solvent,there is added a solution of 43 g of (+)mandelic acid in 550 ml ofabsolute ethanol. After a night at room temperature, the precipitatewhich forms is filtered and crystallized twice from absolute ethanol,recovering each time the crystallized product after standing overnightat room temperature. Thus there is obtained 34.2 g (74%) of the puresalt of (+)mandelic acid with the (+)-2-amino-7-methoxytetralin; m.p.190°-192° C. The mother-liquors of this first crystallization areseparated and used for PREPARATION III hereinbelow. An amount of 34 g ofthe salt thus obtained is suspended in 300 ml of water and the reactionmixture is made alkaline with N sodium hydroxide. The base is extractedwith ethyl acetate, the solution is evaporated to dryness and theresidue is taken up with 260 ml of 48% hydrobromic acid. The reactionmixture is heated with reflux for 3 hours, evaporated to dryness underreduced pressure and the residue thus obtained is taken up with 70 ml ofwater. The aqueous solution is made alkaline with concentrated ammoniumhydroxide, cooled overnight and filtered. Thus, there is obtained 17 gof R(+)-2-amino-7-hydroxytetralin as a monohydrate; SR 58554; m.p.143°-144° C., [alpha]=+85.1° (methanol, c=0.5%). The hydrochloride ofthis product has a rotatory power corresponding to that of theliterature (Molecular Pharmacology 1982, 22, 281-289).

PREPARATION III S(-)-2-amino-7-hydroxytetralin monohydrate, SR 58555

The separated mother-liquors of the first crystallization of the productSR 58554 (PREPARATION II) are evaporated to dryness, the residue thusobtained is suspended in 300 ml of water and the mixture is madealkaline with N sodium hydroxide. The base is extracted with ethylacetate. By operating as described in PREPARATION II and by using thebase thus obtained and (-)mandelic acid as starting products, there isobtained the salt of (-)mandelic acid with (-)-2-amino-7-methoxytetralin(m.p. 189°-191° C.) that, by treatment with N sodium hydroxide, gives 17g of S(-)-2-amino-7-hydroxytetralin as a monohydrate; SR 58555; m.p.143°-144° C., [alpha]=-86.9° (methanol, c=0.5%).

The hydrochloride of this product has a rotatory power corresponding tothat of the literature (Molecular Pharmacology 1982, 22, 281-289).

EXAMPLE 1 (a)N-(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-3-chloromandelamide, SR58534 (mixture of diastereoisomers)

To a suspension of 6.5 g of 2-amino-7-hydroxytetralin hydrobromide(PREPARATION Ic), 4.98 g of 3-chloromandelic acid and 10.69 g ofbenzotriazolyl-N-oxytris-(dimethylamino)phosphonium hexafluorophosphate(BOP) in 120 ml of methylene chloride, there is added 7.44 ml oftriethylamine slowly and the reaction mixture is left to react understirring at room temperature. After 3 hours, 100 ml of a saturatedsodium chloride solution are added and the mixture is left understirring for 30 minutes at room temperature. A volume of 200 ml of ethylacetate is added and the two phases are separated. The organic phase iswashed with a solution of 2N hydrochloric acid, then with a saturatedsodium bicarbonate solution and then with a saturated sodium chloridesolution. The organic phase is dried over sodium sulfate andconcentrated under reduced pressure. There is obtained 12 g of a brownimpure oil which is detected by thin layer chromatography (TLC). The oilis purified by flash chromatography (elution with a 6/4 mixture of ethylacetate/cyclohexane) and all of the fractions are collected. There isobtained 7.5 g (84%) of a chromatographically (TLC) pure pale yellowoil, that solidifies at the pump and is triturated with ether.

(b)(RS,SR)-N-(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-3-chloromandelamide,SR 58535 (less polar diastereoisomer).

An amount of 6 g of the diastereoisomeric mixture SR 58534, obtained asdescribed hereinabove, is dissolved in the warm in 80 ml of ethyl ether.After a night in the refrigerator, a precipitate is obtained that isfiltered. There is obtained 1.4 g of a white solid, that in TLC (elutionwith a 1/1 mixture of ethyl acetate/cyclohexane), corresponds to theless polar spot of the two spots of the mixture SR 58534. Themother-liquors are submitted to a flash chromatography (elution with 1/1mixture of ethyl acetate/cyclohexane). An amount of 1.2 g of a solidproduct corresponding to the less polar product spot, 1.8 g of themixture and 1.9 g of the product corresponding to the more polar productspot, are obtained. An amount of 2.6 g of the product corresponding tothe less polar isomer is crystallized in 60 ml of ethyl acetate toobtain 2.1 g of the first pure isomer; m.p. 172°-174° C.

(c)(RR,SS)-N-(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-3-chloromandelamide,SR 58536 (more polar diastereoisomer)

The more polar isomer obtained as described in (b), SR 58536, is a whiteoil which, in TLC, has the same shift that the (RR) isomer, SR 58533,described in Example 20 hereinbelow. The oil thus obtained (1.9 g),dissolved in a mixture of 15 ml of ethyl acetate and of 5 ml of ethylether is left at room temperature for 48 hours, to obtain thecrystalline SR 58536; m.p. 136°-138° C.

EXAMPLE 2N-(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-4-chloromandelamide

To a mixture of 3.2 g of 2-amino-7-hydroxytetralin hydrobromide(PREPARATION Ic), 2.4 g of 4-chloromandelic acid and 5.2 g ofbenzotriazolyl-N-oxytris-(dimethylamino) phosphonium hexafluorophosphatein 50 ml of methylene chloride, there is added 3.6 ml of triethylamine.The solution obtained is left under stirring at room temperature for 3hours, then a saturated sodium chloride solution is added and themixture is stirred for 30 minutes. The organic phase that separates isevaporated to dryness and an oil is obtained that is dissolved in 200 mlof ethyl acetate. The solution thus obtained is washed twice with 40 mlof a 2N hydrochloric acid, twice with a saturated sodium bicarbonatesolution and, then, with a saturated sodium chloride solution. Thesolution is dried over sodium sulfate, filtered and evaporated todryness. The oil so obtained is chromatogrpahed (elution with a 1/1mixture of ethyl acetate/cyclohexane) and all of the fractions arecollected. An amount of 2.7 g (63%) ofN-(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-4-chloromandelamide isobtained as a diastereoisomeric mixture; m.p. about 170° C. (largeinterval of melting), pure enough for a further reaction. In thismixture, the (RS,SR) and (RR,SS) diastereoisomers are well detectable bychromatography; they are easily separable and obtainable in pure form.

EXAMPLE 3 (a) Mixture of stereoisomers

N-[(2R)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(R)-mandelamide, andN-[(2S)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(R)-mandelamide, SR58542.

To a solution of 10 g of 2-amino-7-hydroxytetralin hydrobromide(PREPARATION Ic), 6.3 g of (R)-mandelic acid and 16 g of BOP in 200 mlof anhydrous methylene chloride, there is added 8.1 g of triethylamineslowly and the solution thus obtained is stirred at room temperature for3 hours. A volume of 100 ml of a saturated sodium chloride solution isadded, the reaction mixture is stirred at room temperature for 30minutes, then 400 ml of ethyl acetate are added, the phases areseparated and the aqueous phase is eliminated. The organic phase iswashed twice with 50 ml of 2N hydrochloric acid, twice with a saturatedsodium bicarbonate solution and, then, the solution is dried over sodiumsulfate, filtered and evaporated to dryness. The oil so obtained ispurified by flash chromatography (elution with a 6/4 mixture of ethylacetate/cyclohexane) and all of the fractions are collected. An amountof 10.5 g (yield 88%) of mandelamide SR 58542 is obtained as a thick oilthat, which in TCL, appears to be constituted by the twodiastereoisomers, the percent of which has not been determined.

(b) N-[(2R or2S)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl](R)-mandelamide, SR 58543,less polar isomer.

An amount of 10.5 g of mixture of diastereoisomers SR 58542, obtained asdescribed hereinabove, is divided in three portions of about 3 g. Eachportion is submitted to a flash chromatography (elution with a 1/1mixture of ethyl acetate/cyclohexane). The fractions, obtained from thethree chromatographies, are collected to give 3.1 g of an oilcorresponding to the less polar spot, 3.2 g of a solid corresponding tothe more polar spot and 2 g of a mixture of the two products. An amountof 3.1 g of the less polar isomer is treated at the mechanical pump anda vitreous solid having an undefined melting point is obtained;[alpha]=-107° (methanol, c=0.5%). Yield of the separation of themixture: 30%. After 24 hours at room temperature, the vitreous solidcrystallizes; it is taken up with ethyl ether and filtered; m.p.157°-159° C. The [alpha] is unchanged.

(c) N-[(2S or2R)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(R)-mandelamide, SR 58544,more polar isomer.

An amount of 3.2 of a white solid corresponding to the more polarisomer, obtained as described in (b), is crystallized from 20 ml ofethyl acetate to give 2.8 g of SR 58544; m.p. 145°-147° C.; [alpha]=+26°(methanol, c=1%).

EXAMPLE 4N-(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-2-(3-chlorophenyl)-2-hydroxyethanamine,SR 58339, mixture of diastereoisomers

To a suspension of 0.9 g of lithium aluminium hydride in 20 ml ofanhydrous tetrahydrofuran, there is slowly added a solution of 1.8 g ofthe N-(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-3-chloromandelamidedescribed in Example 1 (a) (SR 58534) in 30 ml of tetrahydrofuran. Thereaction mixture is heated with reflux for 4 hours, cooled with anice-and-water bath, treated with 2 ml of water, 2 ml of a concentratedsodium hydroxide solution and 10 ml of water again. The mixture isstirred at room temperature for 20 minutes, then 50 ml of ethyl acetateare added thereto. The mixture is filtered on CELITE (registeredTRADEMARK) to break the emulsion. The organic phase which separates isdried over sodium sulfate, filtered and evaporated to dryness. There isobtained 1.2 g of an oil that is purified by flash chromatography(elution with a 9/1 mixture of methylene chloride/methanol). Thepurified base is dissolved in 10 ml of ethyl acetate and, by cooling,0.35 g of SR 58339 base is obtained; m.p. 133°-138° C.; undefinedpercent of the diastereoisomers.

In this mixture, the (RS,SR) and (RR,SS) diastereoisomers are notdetectable by chromatography and they may be separated by othertechniques only.

Its hydrochloride, SR 58339A, is described in Example 8 of the Europeanpatent 211721.

EXAMPLE 5(RS,SR)-N-(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-2-(3-chlorophenyl)-2-hydroxyethanamine,SR 58523.

To a solution of 6 g of SR 58535, obtained as described in Example 1(b), in 60 ml of anhydrous tetrahydrofuran, heated with reflux undernitrogen stream, there is added, during 20 minutes, 4.5 ml of a 10Msolution of the borane-methylsulfide complex, diluted in 20 ml ofanhydrous tetrahydrofuran. After adding dropwise of 40 ml of methanol,the mixture is heated at reflux for other 30 ml minutes, then evaporatedto dryness, taken up with 30 ml of water, 5 ml of concentrated ammoniumhydroxide and 200 ml of ethyl acetate. The organic phase is separated,dried over sodium sulfate and evaporated to dryness. The residue issumbitted to a flash chromatography (elution with a 9/1 mixture ofmethylene chloride/methanol). By crystallization of the solid residue in50 ml of ethyl acetate, 1.2 g of product melting at 180°-184° C. isobtained, that, after recrystallization from 60 ml of ethyl acetate,gives pure SR 58523; m.p. 184°-186° C.

EXAMPLE 6(RR,SS)-2-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-2-(3-chlorophenyl)-2-hydroxyethanamine,SR 58524

By operating as described in Example 5, starting from 4 g of SR 58536obtained as described in Example 1(c), 2.4 g of pure SR 58524,crystallized from isopropanol, are obtained; m.p. 143°-145° C.

EXAMPLE 7N-(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-2-(4-chlorophenyl)-2-hydroxyethanamine,SR 58521, mixture of diastereoisomers

To a suspension of 0.9 g of lithium aluminium hydride in 20 ml ofanhydrous tetrahydrofurane there is added, during 10 minutes undernitrogen stream, a solution of 2.2 g of diastereoisomeric mixture ofN-(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-4-chloromandelamide, asobtained in Example 2, in 30 ml of anhydrous tetrahydrofuran. Thereaction mixture is heated with reflux for 3 hours, then 0.45 g oflithium aluminium hydride is added thereto and the mixture thus obtainedis heated with reflux for 90 minutes. To the mixture cooled at 5° C.,there is added 50 ml of ethyl ether, and, then, 20 ml of water dropwise.The solution is extracted with 100 ml of ethyl acetate, the organicphase is separated, dried over sodium sulfate, filtered and evaporatedto dryness. An oil is obtained that is purified by flash chromatography(elution with a 85/15 mixture of methylene chloride/methanol). A solidproduct in obtained that, crystallized from 20 ml of ethyl acetate,gives 0.7 g of the SR 58521 as a diastereoisomeric mixture; m.p.152°-156° C. (yield 33%). In this mixture, the (RS,SR) and (RR,SR)diastereoisomers are not detectable by chromatography and they can beseparated by other techniques only.

EXAMPLE 8

(a) To a solution of 7 g ofR(+)-2-amino-7-hydroxy-1,2,3,4-tetrahydronaphtalene monohydrate(PREPARATION II), 7.2 g of racemic 3-chloromandelic acid, 16 g of BOP in200 ml of anhydrous methylene chloride, there is added 3.9 g oftriethylamine slowly and the solution thus obtained is stirred at roomtemperature for 3 hours. A volume of 100 ml of a saturated sodiumchloride solution is added. The mixture is stirred at room temperaturefor 30 minutes and 400 ml of ethyl acetate are added thereto. The phasesthus obtained are separated and the aqueous phase is eliminated. Theorganic phase is washed twice with 50 ml of 2N hydrochloric acid, thentwice with a saturated sodium bicarbonate solution and, then, theorganic phase is dried over sodium sulfate, filtered and evaporated todryness. The product thus obtained is purified by flash chromatography(elution with a 6/4 mixture of ethyl acetate/cyclohexane) and all of thefractions are collected to give theN-[(2R)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(RS)-3-chloromandelamide as diastereoisomeric mixture.

(b) An amount of 15 g of the above diastereoisomeric mixture, issubmitted to a flash chromatography (elution with a 1/1 mixture of ethylacetate/cyclohexane). An amount of 4.5 g of a product corresponding tothe less polar spot, 5 g of a product corresponding to the more polarspot and 3 g of a mixture of the two products is obtained. An amount of4.5 g of the less polar isomer is treated at the mechanical pump toobtain theN-[(2R)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(S)-3-chloromandelamide,SR 58588, as a solid having an undefined melting point; [alpha]=+92.5°(methanol, c=1%).

(c) An amount of 5 g of the white solid corresponding to the more polarisomer obtained as described in (b), crystallized from 20 ml of ethylacetate, gives 4.3 g ofN-[(2R)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(R)-3-chloromandelamide,SR 58533; m.p. 143°-147° C.; [alpha]=+35.1°(methanol, c=1%).

EXAMPLE 9

By operating as described in Example 8 and substituting theS(-)-2-amino-7-hydroxy-1,2,3,4-tetrahydronaphtalene monohydrate(PREPARATION III), for theR(+)-2-amino-7-hydroxy-1,2,3,4-tetrahydronaphtalene monohydrate there isobtained:

(a)N-[(2S)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(RS)-3-chloromandelamide,as a mixture of diastereoisomers;

(b)N-[(2S)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(R)-3-chloromandelamide,SR 58587; less polar isomer; undefined melting point; [alpha]=-95°(methanol, c=1%);

(c)N-[(2S)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(S)-3-chloromandelamide,SR 58574; m.p. 145°-146° C.; more polar isomer; [alpha]=-34.2°(methanol, c=1%).

EXAMPLE 10

(a) To a solution of 7.0 g ofR(+)-2-amino-7-hydroxy-1,2,3,4-tetrahydronaphtalene monohydrate(PREPARATION II), 5.8 g of racemic mandelic acid, 15.3 g of BOP in 200ml of anhydrous methylene chloride there is added 3.9 g of triethylamineslowly and the solution thus obtained is stirred at room temperature for3 hours. A volume of 100 ml of a saturated sodium chloride solution isadded. The mixture is stirred for 30 minutes at room temperature and 400ml of ethyl acetate are added thereto. The phases thus obtained areseparated and the aqueous phase is eliminated. The organic phase iswashed twice with 50 ml of 2N hydrochloric acid, then twice with asaturated sodium bicarbonate solution and, then, the organic phase isdried over sodium sulfate, filtered and evaporated to dryness. Theproduct thus obtained is purified by flash chromatography (elution witha 6/4 mixture of ethyl acetate/cyclohexane) and all of the fractions arecollected to give theN-[(2R)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(RS)-mandelamide asdiastereoisomeric mixture.

(b) An amount of 12 g of the above diastereoisomeric mixture issubmitted to a flash chromatography (elution with a 1/1 mixture of ethylacetate/cyclohexane). There is obtained 4 g of a product correspondingto the less polar spot, 4.5 g of a product corresponding to the morepolar spot and 2 g of a mixture of the two products. An amount of 4 g ofthe less polar isomer is treated at the mechanical pump to obtain theN-[(2R)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(S or R)-mandelamide,SR 58561; m.p. 159°-160° C.; [alpha]=+110° (methanol, c=0.5%).

(c) An amount of 4.5 g of the white solid corresponding to the morepolar isomer obtained as described in (b) is crystallized from 20 ml ofethyl acetate. There is obtained 3.9 g ofN-[(2R)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(R or S)-mandelamide;m.p. 145°-147° C.; [alpha]=+26° (methanol, c=1%), identical with theproduct SR 58544 of Example 3 (c).

EXAMPLE 11

By operating as described in Example 10 and substituting theS(-)-2-amino-7-hydroxy-1,2,3,4-tetrahydronaphtalene monohydrate(PREPARATION III) for theR(+)-2-amino-7-hydroxy-1,2,3,4-tetrahydronaphtalene monohydrate, thereis obtained:

(a) N-[(2S)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(RS)-mandelamide;mixture of diastereoisomers;

(b) N-[(2S)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(R orS)-mandelamide; m.p. 157°-159° C.; [alpha]=-107° (methanol, c=0.5%),identical with the product SR 58543 of Example 3(b);

(c) N-[(2S)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(S orR)mandelamide, SR 58559; m.p. 147°-148° C.; [alpha]=-27.5° (methanol,c=0.5%).

EXAMPLE 12

To a solution of 3 g ofN-[(2R)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(S)-3-chloromandelamide,SR 58588, described in Example 8(b), in 40 ml of anhydroustetrahydrofuran, heated with reflux under nitrogen stream, there isadded 2.7 ml of a 10M solution of boranemethylsulfide in 20 ml oftetrahydrofuran, and the refluxing is maintained for 4 hours. To thesolution cooled to room temperature, there is added 25 ml of methanoland the reaction mixture is left under stirring at first at roomtemperature for 30 minutes and then at reflux for 30 minutes. Thesolution is concentrated under reduced pressure and, after filtration,the product is crystallized twice from isopropanol. There is obtained2.1 g (73%) ofN-[(2R)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(2S)-2-(3-chlorophenyl)-2-hydroxyethanamine,SR 58590; m.p. 186°-188° C.; [alpha]=+76° (methanol, c=0.5%).

EXAMPLE 13

By operating as described in Example 12, starting from 4.7 g of SR58533, obtained as described in Example 8(c), a base is obtained as aresidual oil that is purified by flash chromatography (elution with a95/5 mixture of methylene chloride/methanol). The purified base isdissolved in acetone, the solution is filtered and a saturated solutionof hydrogen chloride in isopropanol is added thereto. After filtration,the product is crystallized twice from isopropanol. The product iscooled, filtered and washed with isopropanol and, then, with acetone.There is obtained 3.2 g (65%) ofN-[(2R)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(2R)-2-(3-chlorophenyl)-2-hydroxyethanaminehydrochloride, SR 58572 A; m.p. 203°-205° C.; [alpha]=+36.4° (methanol,c=1%).

EXAMPLE 14

By operating as described in Example 12, starting from 2.5 g of SR58587, obtained as described in Example 9(b), there is obtained 1.6 g(67%) ofN-[(2S)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(2R)-2-(3-chlorophenyl)-2-hydroxyethanamine,SR 58589; m.p. 185°-187° C.; [alpha]=-78.5° (methanol, c=0.5%).

EXAMPLE 15

By operating as described in Example 12 and using as starting product3.44 g of SR 58574, obtained as described in Example 9(c), a base isobtained as an oil that is purified by flash chromatography (elutionwith a 95/5 mixture of methylene chloride/methanol). The purified baseis dissolved in acetone, the solution is filtered and a saturatedsolution of hydrogen chloride in isopropanol is added thereto. Afterfiltration, the product is crystallized twice from isopropanol. Theproduct is cooled, filtered and washed with isopropanol and, then, withacetone to give 1.2 g (34%) ofN-[(2S)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(2S)-2-(3-chlorophenyl)-2-hydroxyethanaminehydrochloride, SR 58575 A; m.p. 203°-205° C.; [alpha]=-35.8° (methanol,c=1%).

EXAMPLE 16

A solution of 2.4 g ofN-[(2R)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(S or R)-mandelamide,SR 58561, obtained as described in Example 10(b), in 100 ml oftetrahydrofuran, is heated with reflux in the presence of 1.85 g oflithium aluminium hydride for 16 hours. After addition of a mixture of 5ml of water in 13 ml of ethanol, the solution is stirred for 15 minutes,then concentrated ammonium hydroxide is added thereto. The product thusobtained is filtered and washed with ethanol. After evaporation todryness, the residue is taken up with ethyl acetate. The resultingmixture is dried over anhydrous sodium sulfate and evaporated todryness. After crystallization of the residue from 15 ml of isopropanol,there is obtained 1 g (44%) ofN-[(2R)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(2S or2R)-2-hydroxy-2-phenylethanamine, SR 58372; m.p. 172°-174° C.;[alpha]=+77.6° (DMF, c=1 %).

EXAMPLE 17

By operating as described in Example 16 and using as starting product2,3 g of SR 58544, obtained as described in Example 10(c), a base isobtained that is dissolved in 50 ml of acetone and the solution is madeacid with a saturated solution of hydrogen chloride in ethanol. Theproduct thus obtained is crystallized by dissolving it in 15 ml ofisopropanol and by precipitation with 15 ml of ethyl ether. There isobtained 0.9 g (36%) ofN-[(2R)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(2R or2S)-2-hydroxy-2-phenylethanamine hydrochloride; m.p. 178°-180° C.;[alpha]=+40.3° (ethanol/eau 1/1, c=2%). This compound corresponds to theproduct SR 58375 A of Example 22 of EP 211721.

EXAMPLE 18

By operating as described in Example 16 and starting from 2.7 g of SR58543, obtained as described in Example 11(b), there is obtained 1 g(40%) of N-[(2S)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(2R or2S)-2-hydroxy-2-phenylethanamine, SR 58374; m.p. 173°-174° C.;[alpha]=-78.3° (DMF, c=1%).

EXAMPLE 19

By operating as described in Example 16, and starting from 3 g of SR58559, obtained as described in Example 11(c), a base is obtained thatis dissolved in 20 ml of acetone. The solution is made acid with asaturated solution of hydrogen chloride in isopropanol. The product thusobtained is crystallized by dissolving it in 8 ml of isopropanol and byprecipitation with 8 ml of ethyl ether. There is obtained 1.55 g (49%)of N-[(2S)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(2S or2R)-2-hydroxy-2-phenylethanamine hydrochloride; m.p. 179°-180° C.;[alpha]=-41.5° (ethanol/water 1/1, c=2%). This compound corresponds tothe product SR 58373A of Example 23 of EP 211721.

EXAMPLE 20

To a suspension of 2.6 g of (R)-2-amino-7-hydroxytetralin hydrochloride(PREPARATION II), 2.4 g of (R)-3-chloromandelic acid (Bull. Soc. Chim.Fr., 1973, 12, 3330) and 5.2 g of BOP in 60 ml of anhydrous methylenechloride, there is added 3.6 ml of triethylamine slowly, then thesolution thus obtained is stirred at room temperature for 3 hours. Afteraddition of 50 ml of a saturated sodium chloride solution, the reactionmixture is stirred for 30 minutes at room temperature, then 200 ml ofethyl acetate are added thereto and the phases are separated. Theorganic phase is washed twice with 30 ml of a 2N hydrochloric acidsolution, then twice with 30 ml of a saturated sodium chloride solution.The organic solution is dried over sodium sulfate, filtered andevaporated to dryness. The oil thus obtained is purified by flashchromatography (eluent 55/45 mixture of ethyl acetate/cyclohexane). Adoughy solid is obtained that is taken up with 20 ml of ethyl ether fromwhich the product crystallizes. After addition of 10 ml of cyclohexane,the solution is filtered, washed with a 2/1 mixture of cyclohexane/ethylether and dried under reduced pressure at 50° C. to give 2.4 g (55%) ofa stereoisomer that is pure according to ¹³ C RMN at 60 MHz; m.p.132°-134° C., [alpha]=+24.9° (methanol, c=1%). In TLC this product hasthe same shift of the product of Example 1(c), SR 58536 (RR,SS) and noimpurity corresponding to the Rf of SR 58535 (RS,SR) of Example 1(b)(elution with 1/1 ethyl acetate/cyclohexane). After a furtherpurification by chromatography, there is obtained the enantiomericallyand chemically pureN-[(2R)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(R)-3-chloromandelamide;m.p. 143°-147° C., [alpha]=+35.1° (methanol, c=1%). This product isidentical with the compound SR 58533 of Example 8(c), the R,Rconfiguration of which is thus confirmed.

EXAMPLE 21

By operating as described in Example 20 substituting the(S)-3-chloromandelic acid (Bull. Soc. Chim. Fr., 1973, 12, 3330) for the(R)-3-chloromandelic acid, theN-[(2R)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(S)-3-chloromandelamideis obtained as a solid having an undefined melting point; [alpha]=+92.5°(methanol, c=1%). This product is identical with the compound SR 58588of Example 8(b), the (R, S) configuration of which is thus confirmed.

EXAMPLE 22

To a mixture of 3.6 g of (R)-3-chloromandelic acid, 3.5 gS(-)-2-amino-7-hydroxy-1,2,3,4-tetrahydronaphtalene monohydrate(PREPARATION III) and 7.7 g of BOP in 60 ml of anhydrous methylenechloride under nitrogen stream, there is added 2.7 ml of triethylamine.The solution obtained is stirred for 5 hours at room temperature, then400 ml of ethyl acetate are added thereto and the organic phase iswashed with water, separated and evaporated to dryness. The residue thusobtained is treated with 150 ml of N sodium hydroxide and extracted withethyl ether. The organic phase is eliminated. The aqueous phase isacidified with concentrated hydrochloric acid and extracted with ethylacetate. The organic phase thus obtained is washed with water, driedover sodium sulfate, filtered and evaporated to dryness. The oil thusobtained is purified by flash chromatography (elution with a 70/30mixture of ethyl acetate/cyclohexane). An amount of 4 g (63%) ofN-[(2S)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(R)-3-chloromandelamideis obtained as a very thick whittish oil that is treated with petroleumether; a solid having an undefined melting point is obtained;[alpha]=-95° (methanol, c= 1%). This product is identical with thecompound SR 58587 of Example 9(b), the (S, R) configuration of which isthus confirmed.

EXAMPLE 23

By operating as described in Example 22 and substituting the(S)-3-chloromandelic acid for the (R)-3-chloromandelic acid, there isobtained theN-[(2S)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(S)-3-chloromandelamide;m.p. 145°-146° C.; [alpha]=-34.2° (methanol, c=1%). This product isidentical with the compound SR 58574 of Example 9(c), the (S,S)configuration of which is thus confirmed.

EXAMPLE 24

By operating as described in Example 22 and replacing the(R)-3-chloromandelic acid by an equimolecular amount of (R)-mandelicacid there is obtained theN-[(2S)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(R)-mandelamide; m.p.159°-160° C.; [alpha]=-113° (methanol, c=0.5%). This product isidentical with the compound SR 58543 of Examples 3(b) and 11(b), the (S,R) configuration of which is thus defined.

EXAMPLE 25

By operating as described in Example 22 and replacing the(R)-3-chloromandelic acid by an equimolecular amount of (S)-mandelicacid, there is obtained theN-[(2S)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(S)-mandelamide; m.p.147°-148° C.; [alpha]=-27.5° (methanol, c=0.5%). This product isidentical with the compound SR 58559 of Example 11(c), to which the(S,S) configuration is thus finally assigned.

EXAMPLE 26

By operating as described in Example 22 and replacing the(R)-3-chloromandelic acid by an equimolecular amount of (R)-mandelicacid and the S(-)-2-amino-7-hydroxy-1,2,3,4-tetrahydronaphtalenemonohydrate by the R(+)-2-amino-7-hydroxy-1,2,3,4-tetrahydronaphtalenemonohydrate, there is obtained theN-[(2R)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(R)-mandelamide; m.p.145°-147° C.; [alpha]=+26° (methanol, c=1%). This product is identicalwith the compound SR 58544 of Examples 3(c) and 10(c), to which the(R,R) configuration is thus finally assigned.

EXAMPLE 27

By operating as described in Example 22 and replacing the(R)-3-chloromandelic acid by an equimolecular amount of (S)-mandelicacid and the S(-)-2-amino-7-hydroxy-1,2,3,4-tetrahydronaphthalenemonohydrate by the R(+)-2-amino-7-hydroxy-1,2,3,4-tetrahydronaphtalenemonohydrate, there is obtained theN-[(2R)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(S)-mandelamide; m.p.159°-160° C.; [alpha]=+110° (methanol, c=0.5%). This product isidentical with the compound SR 58561 of Example 10(b), the (R, S)configuration of which is thus defined.

EXAMPLES 28 A 31

By submitting the products of Examples 20 to 23 to a reduction withborane-methylsulfide as described in Example 12, the following productsare obtained:

N-[(2R)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(2R)-2-(3-chlorophenyl)-2-hydroxyethanaminehydrochloride, identical with compound SR 58572 A of Example 13, the(R,R) configuration of which is confirmed (Example 28);

N-[(2R)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(2S)-2-(3-chlorophenyl)-2-hydroxyethanamine,identical with compound SR 58590 of Example 12, the (R, S) configurationof which is thus confirmed (Example 29);

N-[(2S)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(2R)-2-(3-chlorophenyl)-2-hydroxyethanamine,identical with compound SR 58589 of Example 14, the (S, R) configurationof which is thus confirmed (Example 30);

N-[(2S)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(2S)-2-(3-chlorophenyl)-2-hydroxyethanaminehydrochloride, identical with compound SR 58575A of Example 15, the(S,S) configuration of which is thus confirmed (Example 31).

EXAMPLES 32 A 35

By submitting the products of Examples 24 to 27 to a reduction withlithium and aluminium hydride as described in Example 16, the followingproducts are obtained:

N-[(2S)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(2R)-2-hydroxy-2-phenylethanamine,identical with compound SR 58374 of Example 18, the (S, R) configurationof which is thus defined (Example 32);

N-[(2R)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(2R)-2-hydroxy-2-phenylethanaminehydrochloride, identical with compound SR 58375 A of Example 17 the (R,S) configuration of which is thus defined (Example 33)

N-[(2S)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(2S)-2-hydroxy-2-phenylethanaminehydrochloride, identical with compound SR 58373 A of Example 19, towhich the (S,S) configuration is finally assigned (Example 34);

N-[(2R)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(2S)-2-hydroxy-2-phenylethanamine,identical with compound SR 58372 of Example 16, the (R, S) configurationof which is thus defined (Example 35).

EXAMPLE 36

A mixture of 15.8 g ofN-[(2S)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(R)-mandelamide,obtained according to Example 3(b), 7.1 ml of ethyl bromoacetate, 22 gof anhydrous potassium carbonate and 1 g of potassium iodide in 600 mlof anhydrous acetone, is heated with reflux and with stirring for 5hours and a half. The reaction mixture is filtered, evaporated todryness and the oil which separates is left to crystallize. The solid soobtained is purified by flashchromatography (elution with a 1/1 mixtureof ethyl acetate/cyclohexane). The solid on the column is taken up andtreated with 20 ml of ethyl ether, filtered and crystallized from ethylacetate to give 11.5 g ofN-[(2S)-7-carbethoxymethoxy-1,2,3,4-tetrahydronaphth-2-yl]-(R)-mandelamide,SR 58638; m.p. 115°-117° C.; [alpha]=-98.3° (methanol, c=1%). Yield:57%.

EXAMPLE 37

To a solution of 5 g ofN-[(2S)-7-carbethoxymethoxy-1,2,3,4-tetrahydronaphth-2-yl]-(R)-mandelamide,Example 36, in 50 ml of anhydrous tetrahydrofuran, there is added,dropwise, 2.6 ml of a 10M solution of borane-methylsulfide in 10 ml ofanhydrous tetrahydrofuran under nitrogen stream at 0° C. temperatureover a period of 10 minutes and the reaction mixture is left to stand atroom temperature overnight. The borane-methylsulfide that has notreacted is destroied by a cautious addition of 30 ml of absolute ethanoland by heating with reflux for 30 minutes. The solution is evaporated todryness and submitted to a flash chromatography (elution with a 85/15mixture of ethyl acetate/methanol). There are obtained two products thatare taken up with ethyl ether.

The less polar product, after crystallization from ethyl acetate, gives1.2 g ofN-[(2S)-7-carbethoxymethoxy-1,2,3,4-tetrahydronaphth-2-yl]-(2R)-2-hydroxy-2-phenylethanamine,SR 58639; m.p. 108°-111° C.; [alpha]=-78.65° (methanol, c=1%). The yieldof SR 58639 is 25.2%. The global yield starting fromN-[(2S)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(R)-mandelamide is14.36%.

The more polar product, after crystallization from ethyl acetate, gives0.5 g ofN-[(2S)-7-(2-hydroxyethoxy-1,2,3,4-tetrahydronaphth-2-yl]-(2R)-2-hydroxy-2-phenylethanamine,SR 58640; m.p. 94°-96° C.; [alpha]=-83.68° (methanol, c=1%).

EXAMPLE 38

By operating as described in Example 37, and using the same quantitiesof reagents, but heating with reflux for 3 hours, there is obtained:

0.8 g ofN-[(2S)-7-carbethoxymethoxy-1,2,3,4-tetrahydronaphth-2-yl]-(2R)-2-hydroxy-2-phenylethanamine,SR 58639, and

1.8 g ofN-[(2S)-7-(2-hydroxyethoxy)-1,2,3,4-tetrahydronaphth-2-yl]-(2R)-2-hydroxy-2-phenylethanamine,SR 58640, identical with the compounds of Example 37.

The latter compound, SR 58640, has a good activity on the intestinalmotility in the rat isolated colon test (EP 255 415).

We claim:
 1. A mandelamide of formula ##STR10## wherein X is hydrogen, ahalogen, a trifluoromethyl group or a lower alkyl group and R^(o) ishydrogen or a methyl group substituted by a carboxy or lower carbalkoxygroup.
 2. A compound according to claim 1 which isN-(7-hydroxy-1,2,3,4-tetrahyronaphth-2-yl)-3-chloromandelamide.
 3. Acompound according to claim 1 which is(RS,SR)-N-(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-3-chloromandelamide.4. A compound according to claim 1 which is(RR,SS)-N-(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)-3-chloromandelamide.5. A compound according to claim 1 which isN-[(2R)-7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-(R)-3-chloromandelamide.6.N-[(2S)-7-hydroxy-1,2,3,4-tetrahydronaphth-2yl]-(R)-3-chloromandelamide.7.N-[(2S)-7-carbethoxymethoxy-1,2,3,4-tetrahydronaphth-2yl]-(R)-mandelamide.